FDA Approves Merck’s First-in-Class HIF-2α Inhibitor WELIREG™ (belzutifan) for VHL Disease-Associated Tumors – A Nobel Prize-Linked Targeted Therapy
MSD
Pharmaceutical R&D and Manufacturer
FDA
U.S. Food and Drug Administration
Welireg (Image source: medpagetoday.net)
MSD (Merck & Co.) recently announced that the U.S. Food and Drug Administration (FDA) ApprovedWelireg (belzutifan, development code: MK-6482), this drug is aHypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, for the treatment of adult patients with von Hippel-Lindau disease (von Hippel-Lindau disease, VHL syndrome, VHL disease) who do not require immediate surgery, and who require treatment for VHL syndrome-associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrineTumor（pNET）。
Welireg is the first HIF-2α inhibitor therapy approved by the U.S. FDA., the drug was approved through the priority review program. Previously,FDAWelireg has been granted Breakthrough Therapy Designation (BTD) and Orphan Drug Designation (ODD). As a HIF-2α inhibitor, Welireg can reduce processes associated with cell proliferation, angiogenesis, andTumorTranscription and expression of growth-related HIF-2α target genes. Notably,The research on VHL biology that led to the discovery of HIF-2α was awarded the 2019 Nobel Prize in Physiology or Medicine.
Welireg is a novel drug in MSD's oncology pipeline, asThe first and only systemic therapy approved for the treatment of patients with VHL syndrome, this drug expands MSD'sTumorStudy Investment Portfolios.VHL syndrome is a rare and severeHereditydisease, associated with a high risk of developing cancer in multiple organs. Cancer remains one of the leading causes of death among patients with VHL syndrome.
Prior to Welireg, there were no approved systemic therapies for the treatment of VHL-associated tumors. In the Phase 2 Study-004, patients with VHL-associated tumors treated with Welireg demonstrated a high response rate and durable responses.FDAThe approval of Welireg marks a significant advance, introducing a systemic therapy,has the potential to change certain types of VHL-related`Tumor`The patient's current treatment regimen.
Regarding dosing, the recommended dose of Welireg (40 mg tablets) is 120 mg once daily until disease progression or unacceptable toxicity. It should be noted that the drug label for Welireg carries a boxed warning indicating that use during pregnancy may cause embryo-fetal harm. Pregnancy status must be verified prior to initiating Welireg. Welireg can render certain hormonal contraceptives ineffective. Physicians prescribing Welireg should inform patients of these risks and the necessity of using effective non-hormonal contraception.
Dr. Scot Ebbinghaus, Vice President of Clinical Research at MSD Research Laboratories, stated: “Welireg is the first and only approved treatment targeting specific types of VHL-associated`Tumor`The systemic therapy for patients represents an important new treatment option for those affected by this rare disease. TodayFDA"The approval of Welireg marks a significant milestone, reflecting MSD's commitment to providing innovative treatment options to more patients."
Study-004 Data (Click image to enlarge)
This approval is based on data from the open-label Phase 2 Study-004 (NCT03401788). The study results demonstrated that treatment with Welireg yielded durable responses in patients with VHL-associated RCC (n=61), VHL-associated CNS hemangioblastoma (n=24), and VHL-associated pNET (n=12).
Specific efficacy data are as follows: (1)In patients with VHL-associated RCC, the confirmed objective response rate (ORR) was 49%, respectively.(95% CI: 36-62), all partial responses (PR); median duration of response (DoR) was not reached (range: 2.8+ to 22.3+ months); among responders (n=30), 56% (n=17/30) remained in response for at least 12 months, and the median time to response (TTR) was 8 months (range: 2.7 to 19 months). (2)In patients with VHL-associated CNS hemangioblastoma, the ORR was 63% (95% CI: 41-81)., the complete response rate (CR) was 4% (n=1) and PR was 58% (n=14), median DoR was not yet reached (range: 3.7+ to 22.3+ months); among responders, 73% (n=11/15) maintained response for at least 12 months, with a median TTR of 3 months (range: 3-11 months). (3)In patients with VHL-associated pNETs, the ORR was 83%.(95% CI: 52-98), CR was 17% (n=2), PR was 67% (n=8), median DoR was not reached (range: 10.8+ to 19.4+ months); among responders, 50% (n=5/10) maintained response at ≥12 months, median TTR was 8 months (range: 3-11 months).
Regarding safety, 15% of patients treated with Welireg experienced serious adverse events, includingAnemia, hypoxia, hypersensitivity reactions, retinal detachment, and central retinal vein occlusion (1 case each). 3.3% of patients permanently discontinued treatment due to adverse reactions. The adverse reactions leading to permanent discontinuationAdverse Reactionswere dizziness and opioid overdose (1.6% each).
Dose interruption of Welireg due to adverse reactions occurred in 39% of patients. Adverse reactions requiring dose interruption that occurred in >2% of patients included fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reduction of Welireg due to adverse reactions occurred in 13% of patients. The most frequently reported requiring dose reductionAdverse Reactionswas fatigue (7%).
In patients treated with Welireg, the most commonAdverse Reactions(≥25%), including laboratory abnormalities, including: decreased hemoglobin (93%), anemia (90%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased blood glucose (34%), and nausea (31%).
Chemical structure of belzutifan (MK-6482) (Image source: medchemexpress.com)
VHL syndrome is a rareHereditydisease, affecting one in every 36,000 individuals (approximately 200,000 cases worldwide, with 10,000 in the United States alone). Patients with VHL syndrome are at risk of developing benign vascular`Tumor`as well as the risk of various cancers, including renal cell carcinoma (RCC). Up to 70% of patients with VHL syndrome develop RCC, which is the leading cause of death in patients with VHL syndrome.
The VHL gene is a critical tumor suppressor gene, and its mutations were first identified in patients with von Hippel-Lindau (VHL) syndrome. The VHL protein functions as a tumor suppressor, and its inactivation can aberrantly activate hypoxia-inducible factor-2α (HIF-2α) in cancer patients. This inactivation of the VHL tumor suppressor protein is observed in over 90% of ccRCC tumors, leading to the accumulation and activation of hypoxia-inducible factor (HIF) proteins within cancer cells. This erroneously signals a hypoxic state, which subsequently activates angiogenesis and stimulates benign and malignant...Tumorgrowth.
The active ingredient of Welireg is belzutifan (MK-6428), which is aA novel, potent, selective, oral HIF-2α inhibitor that targets and inhibits HIF-2α, blocking cell growth and proliferation, and preventing abnormal angiogenesis.Belzutifan was developed by Peloton Therapeutics, which MSD acquired in May 2019 for an upfront payment of $1.05 billion and milestone payments of $1.15 billion.
Currently, belzutifan is being evaluated in multiple clinical trials. In addition to treating VHL-associatedTumorIn addition to the Phase 2 Study-004 (NCT03401788) in patients, the clinical development program for belzutifan also includes a Phase III trial for the treatment of advanced RCC (MK-6482-005; NCT04195750) and a Phase I/II dose-escalation and dose-expansion trial for the treatment of advanced solid tumors, including advanced renal cancer (NCT02974738).